Device And Method For Diffusing High Concentration NO With Inhalation Therapy Gas

ABSTRACT

Systems and methods of the present invention can enable high concentration NO to be delivered into ventilator breathing circuits, via a diffusing device, without generating undesirably large amounts of NO2.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. § 120 of U.S. patentapplication Ser. No. 15/281,512, filed Sep. 30, 2016, which claims thebenefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No.62/235,798, filed Oct. 1, 2015, the entire contents of which areincorporated herein by reference in their entirety.

TECHNICAL FIELD

Principles and embodiments of the present invention relate generally toa device for combining nitric oxide (NO) with other gases beingadministered to a patient for inhalation therapy.

BACKGROUND

A number of gases have been shown to have pharmaceutical action inhumans and animals. One such gas is nitric oxide (NO) that, wheninhaled, acts to dilate blood vessels in the lungs, improvingoxygenation of the blood and reducing pulmonary hypertension. In thefield of inhalation therapy for various pulmonary conditions such asacute pulmonary vasoconstriction, hypertension and thromboembolism, orinhalation injury, treatment has included the use of the therapeutic gasNO supplied from a gas cylinder. More specifically, this gaseous NO forinhalation therapy is supplied to a patient from a high pressure gascylinder containing NO. For example, such an approach is disclosed inU.S. Pat. No. 5,558,083 entitled “Nitric Oxide Delivery System”, whichis incorporated herein by reference in its entirety.

Inhaled nitric oxide (INO) therapy, generally speaking, involvesdelivering a concentration of NO, at a set dose, to mechanicallyventilated patients. NO delivery systems of this type (wrap-aroundstyle) can sense fresh gas flow in the inspiratory limb of themechanical ventilator, and ratio-metrically deliver NO from sourcecylinders into the inspiratory limb of the ventilator, via an injectormodule, to achieve a prescribed patient dose.

Typically speaking, the concentration of the NO source (e.g., from thesource cylinders) may be about 800 ppm NO. As discussed above, this NOsource gas at 800 ppm can be proportionally delivered (e.g.,ratio-metrically delivered) into fresh gas flow such that theconcentration of NO in the fresh gas flow is about 5 to 80 ppm.

Although INO therapy has many benefits, it has been found that whendelivering NO into fresh gas flow, nitrogen dioxide (NO₂), a toxic gas,can be generated by reacting with O₂ in fresh gas flow. Morespecifically, the formation of nitrogen dioxide is proportional to thesquare of the NO concentration multiplied by the concentration of O₂.

The kinetics and rate equation for the conversion of NO to NO₂ is givenby:

2NO→N₂O₂

N₂O₂+O₂→2NO₂

Thus, giving a formation rate of NO₂=k[NO]²[O₂], where k is in units ofL·mol⁻¹·s⁻¹, or in partial pressures for the gases.

Accordingly, the amount of NO₂ produced (ppm NO₂) is related to thesquare of the NO concentration and is linear to the oxygenationconcentration and time.

In light of the above, NO delivered into a ventilator breathing circuitfrom a low concentration NO source (e.g., 100 ppm, 400 ppm, and 800 ppmNO cylinders) may not result in undesirably high amounts of NO₂, forexample >1 ppm; however, following the above kinetics, the use of NOdelivered into a ventilator breathing circuit from a high concentrationsource (e.g., 2000 ppm, 5000 ppm, and 10,000 ppm NO cylinders) would beexpected to generate an unacceptable amount of toxic NO₂, for example >1ppm NO₂ generated when providing a 40 ppm NO dose with 60% O₂.Theoretically, for the same NO therapy dose, NO₂ from a 5000 ppm sourcegas may have a formation rate to 39 times greater than an 800 ppmsource.

Some have attempted to address this problem using varying techniques;however, these techniques may not work in specific systems, may not workwhen delivering high concentration NO, may not work at all, or can failto address the actual cause of NO₂ generation and/or underlying factorsin NO₂ generation not previously appreciated. Accordingly a need existsfor systems and methods of reducing NO₂ generation that work in specificsystems, address the actual cause of NO₂ generation and/or theunderlying factors not previously appreciated.

SUMMARY

Systems and methods of the present invention can be used to reduce NO₂generated when, for example, being delivered into fresh gas flow in aventilator breathing circuit. Further, systems and methods of thepresent invention can enable high concentration NO to be delivered intoventilator breathing circuits, via a diffusing device, withoutgenerating undesirably large amounts of NO₂ for example >1 ppm NO₂ for adose of 40 ppm NO with 100% O₂. Use of high concentration NO sources(e.g., 2000, 4880, 10,000 ppm NO cylinders) can provide benefits suchas, but not limited to, the use of smaller NO gas cylinders, whichallows increased portability and introducing smaller volumes of the highconcentration gas into the ventilator gas stream, and less dilution ofoxygen-enriched Fresh Gas Flow (FGF) by the NO and carrier N₂ gases. Ithas surprisingly been found that introduction of smaller NO volumes withdiffusion at equivalent or higher rates can generate less NO₂ overallwith shorter diffusion time associated with smaller gas volume. Theissues addressed herein relate to at least rapidly reducing NOconcentration before large concentrations of NO₂ can be formed.

There are several ways to address the above problems, including reducingthe time that high concentrations of NO exist within the ventilator gasstream, which may be achieved by increasing the rate that the NOdiffuses into the other gases, and/or decreasing the residence time ofthe high concentration NO in the ventilator breathing circuit prior tobeing rapidly diffused. This reduction in time may be achieved at theimmediate point of NO injection, through methods minimizing transient NOconcentration time from high (source) concentration to low (set dose)concentration. Very rapid NO concentration reduction from source to setdose at the immediate point of injection significantly reduces NO₂generation, and may be accomplished through a variety of methods,including but not limited to methods such as gas mixing, gas diffusion,thermal effects, intersecting gas stream orientations, intersecting gasstream velocities, or any combinations thereof. The transient NOconcentration time, or time NO resides in FGF substantially above setdose, is the time NO₂ can be generated at a significantly higher ratecompared with the time NO resides in FGF at or near set dose. Stateddifferently, it is acknowledged that NO₂ continues to be generated evenafter the homogeneous NO concentration is achieved. However, NO₂generation in regions where NO concentration nears set dose is linearwith O₂ concentration and time, and therefore at a significantly lowerrate in comparison to NO₂ generation observed during the time oftransient NO concentration.

Principles and embodiments of the present invention relate generally toa device and methods of treating patients with NO inhalation therapyinvolving a high concentration NO source. However, although the methods,systems and devices described herein are discussed in the context ofhigh concentration NO sources, the methods, systems and devicesdescribed herein can also be applied to lower concentration NO sources,such as those at or below 800 ppm NO.

Aspects of the present invention relate to a device that combines a gasstream comprising NO and a fresh gas flow stream comprising molecularoxygen (O₂) for delivery to a patient, wherein the diffusing of NO andO₂ occurs sufficiently rapidly that production of NO₂ is minimized, soless than 1 ppm of NO₂ is delivered to a patient and/or generated in theventilator circuit.

In various embodiments, the concentration of NO in the patient inspiredgas is in the range of about 1 ppm to about 80 ppm, or alternatively 5ppm to about 80 ppm, or about 20 ppm to about 60 ppm. Other exemplary NOconcentrations for the set dose include about 1 ppm, about 2 ppm, about3 ppm, about 4 ppm, about 5 ppm, about 10 ppm, about 15 ppm, about 20ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 45ppm, about 50 ppm, about 55 ppm, about 60 ppm, about 65 ppm, about 70ppm, about 75 ppm or about 80 ppm.

In various embodiments, the concentration of the NO source is in therange of about 200 ppm to about 10,000 ppm, or about 400 ppm to about10,000 ppm, or greater than 800 ppm to about 10,000 ppm, or about 1,000ppm to about 5,500 ppm. Other exemplary NO concentrations of the NOsource include about 200 ppm, about 300 ppm, about 400 ppm, about 500ppm, about 600 ppm, about 700 ppm, about 800 ppm, about 1000 ppm, about1200 ppm, about 1500 ppm, about 2000 ppm, about 2200 ppm, about 2400ppm, about 2440 ppm, about 2500 ppm, about 3000 ppm, about 3500 ppm,about 4000 ppm, about 4500 ppm, about 4800 ppm, about 4880 ppm, about5000 ppm, about 6000 ppm, about 7000 ppm, about 8000 ppm, about 9000 ppmor about 10,000 ppm.

In various embodiments, NO₂ levels produced using a high concentrationNO source (such as a 4880 or a 5000 ppm NO source) can be comparable toor less than those produced with lower concentration NO sources (such asa 200 ppm or 800 ppm NO source).

Aspects of the present invention relate to a method of rapid NOconcentration reduction from source concentration to set dose, byincreasing the mixing and/or diffusing efficiency of NO within arespiratory gas, fresh gas flow, for the treatment of various pulmonaryconditions.

Aspects of the present invention relate to a diffusing device forinjecting a high concentration gas into a transverse gas streamcomprising a body comprising a wall having a thickness, an outersurface, and an inner surface surrounding a hollow internal region, aprojection extending from the inner surface of the body, and aninjection channel passing through the wall and projection to aninjection port located where the velocity of the fresh gas flow is high(e.g., centrally located in the cross section of the body, wheredirected to be higher, etc.). As used herein, a “high velocity” of gasflow is any portion of a gas flow that has a higher velocity than thevelocity of the gas flow that is at or close to an edge boundary (e.g.the walls of a tube). Due to the no-slip condition, gas flow at the edgeboundary has a velocity of zero, and due to the viscosity of the gas,the gas flow closer to the zero-velocity gas has a lower velocity thanthe gas flow that is farther from the edge boundary and thezero-velocity gas.

Accordingly, in exemplary embodiments, the high concentration gas isinjected into a portion of the transverse gas stream that is a distancefrom the edge boundary (e.g. wall).

Aspects of the present invention relate to a diffusing device forinjecting a high concentration gas (e.g., greater than 800 to 10,000 ppmNO) into a transverse gas stream, comprising a body comprising a wallhaving a thickness, an outer surface and an inner surface, a projectionextending from the inner surface of the annular body, a tapered sectioncomprising a wall having a thickness, an outer surface and an innersurface, an inlet end having a first diameter, and an outlet end havinga second diameter opposite the inlet end, wherein the second diameter issmaller than the first diameter, and wherein the tapered section isconnected to and suspended from the projection, such that the projectionforms a support for the tapered section, and an injection channelpassing through the projection to an injection port in the inner surfaceof the tapered section. In exemplary embodiments, gas flow from theinjection channel, and in turn, out of the injection port, can bedirected to flow into the transverse gas stream where the fastest gasvelocity exists.

In one or more embodiments, the diffusing device for injecting a highconcentration gas (e.g., greater than 800 to 10,000 ppm NO) into atransverse gas stream does not comprise a tapered section suspended fromthe projection. In various embodiments, the projection extends radiallyfrom the inner surface of the annular body into approximately the centerof the open volume surrounded by the cylindrical wall, and an injectionchannel passes through the projection to an injection port.

In various embodiments, the injection port has an inside diameter in therange of about 0.58 mm (0.023 in.) to about 4.75 mm (0.187 in.), orabout 0.8 mm (0.031 in.) to about 2.4 mm (0.094 in.), or about 1.12 mm(0.044 in.) to about 2.29 mm (0.090 in.), or about 1.83 mm (0.072 in.).Exemplary lower limits include about 0.58 mm, about 0.6 mm, about 0.7mm, about 0.8 mm, about 0.9 mm, about 1 mm, about 1.1 mm, about 1.2 mm,about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm andabout 1.8 mm. Exemplary upper limits include about 4.75 mm mm, about 4.5mm, about 4 mm, about 3.5 mm, about 3 mm, about 2.5 mm, about 2.4 mm,about 2.29 mm, about 2.2 mm, about 2.1 mm, about 2 mm and about 1.9 mm.

In one or more embodiments, the diffusing device may be configured anddimensioned to be inserted into and in fluid communication with abreathing circuit scaled for a neonate, a pediatric, or an adult with acorresponding and appropriate ventilator tube size. In variousembodiments, the annular body has an outside diameter in the range ofabout 10 mm to about 25 mm, and an inside diameter in the range of about10 mm to about 25 mm, wherein the inside diameter is smaller than theoutside diameter by the thickness of the cylindrical wall.

In various embodiments, the thickness of the cylindrical wall ‘C’ is inthe range of about 1 mm to about 3.175 mm, or about 1.5 mm.

In various embodiments, the diffusing device is configured anddimensioned for insertion into respiratory tubing, such as for aventilator breathing circuit.

In various embodiments, the first diameter is in the range of about 6 mmto about 18 mm, and the second diameter is in the range of about 3.17 mmto about 9.5 mm, where the first diameter is greater than the seconddiameter.

In various embodiments, the tapered section is symmetrical around anaxis, and the injection channel forms an angle in the range of about 60°to about 120° with the axis of the tapered section.

In various embodiments, the tapered section is funnel shaped.

In various embodiments, the tapered section is truncated cone shaped.

In various embodiments, the tapered section is bell shaped.

Aspects of the present invention relate to a method of diffusing a highconcentration gas into a transverse gas stream, comprising passing atleast a portion of a first gas through a tapered section comprising awall having a thickness, an outer surface and an inner surface, an inletend having a first diameter, and an outlet end having a second diameteropposite the inlet end, wherein the second diameter is smaller than thefirst diameter and passing a second gas stream through an injectionchannel to an injection port in the inner surface of the taperedsection, wherein the second gas stream enters and at least partiallydiffuses with the first gas stream within the tapered section.

In various embodiments, the method further comprises passing at least aportion of the first gas around at least a portion of the outer surfaceof the tapered section, wherein the tapered section is within an annularbody having an outer surface and an inner surface, and an insidediameter that is larger than the first diameter of the tapered section.

In various embodiments, a support connects the annular body to thetapered section the injection, so the second gas passing through theinjection channel passes through the support to the injection port.

In various embodiments, the second gas stream initially enters the firstgas stream at an angle in the range of about 60° to about 120°.

In various embodiments, the first gas is a breathable gas comprisingmolecular N₂ and molecular O₂, and the second gas comprises molecular NOand molecular N₂.

In various embodiments, the concentration of NO in the second gas is inthe range of greater than 800 ppm to about 5,500 ppm.

In various embodiments, the first gas enters the annular body at a flowrate in the range of about 0 liters per minute (SLPM) to about 120 SLPM,or about 0.5 SLPM to about 60 SLPM, or about 0.5 SLPM to about 2 SLPM.

In various embodiments, the first gas (e.g., FGF) is a breathable gascomprising molecular N₂ and molecular O₂, and the second gas comprisesmolecular NO at a concentration in the range of greater than 1000 ppm toabout 5,500 ppm, and the second gas exits the injection port at a flowrate in the range of about 0.05 milliliters per minute (SMLPM) to about2 SLPM, or about 0.1 SMLPM to about 1 SLPM.

Oxygen concentration in patient ventilator circuits may be set to avalue over the continuous range from medical air (21% O₂) to medicaloxygen (100% O₂), but may be generally elevated to 60% for patientsreceiving INO therapy.

In various embodiments, the flow rate of the second gas is linearlyproportional to the flow rate of the first gas.

In various embodiments, the velocity of the first gas is greater at thesecond diameter of the tapered section than the velocity of the firstgas at the first diameter of the tapered section, wherein the second gasenters the first gas at a point of greater or equal velocity.

Aspects of the invention also relate to a method of diffusing a highconcentration gas into a transverse gas stream, comprising passing atleast a portion of a first gas through a hollow internal region of abody having an inner surface surrounding the hollow internal region; andpassing a second gas stream through an injection channel to an injectionport projecting into the hollow internal region of the body, wherein thesecond gas stream enters and at least partially diffuses with the firstgas stream within the hollow internal region

BRIEF DESCRIPTION OF THE DRAWINGS

Further features of embodiments of the present invention, their natureand various advantages will become more apparent upon consideration ofthe following detailed description, taken in conjunction with theaccompanying drawings, which are also illustrative of the best modecontemplated by the applicants, and in which like reference charactersrefer to like parts throughout, where:

FIGS. 1A-F show the NO₂ generated after injecting NO intooxygen-enriched air under various conditions;

FIG. 1G shows the NO₂ generated at various points downstream from thepoint of NO injection;

FIGS. 2A-C illustrate an exemplary embodiment of a mixing device havinga plurality of blades;

FIGS. 3A-C illustrate an exemplary embodiment of a tapered sectionhaving a plurality of angled fins;

FIGS. 4A-C illustrate an exemplary embodiment of a mixing device havinga plurality of plates;

FIGS. 5A-C illustrate an exemplary embodiment of a mixing device havinga plurality of curved blades;

FIGS. 6A-C illustrate an exemplary embodiment of a mixing device havinga plurality of curved blades and an injection channel at a taperedsection;

FIG. 7 illustrates an exemplary velocity distribution of a gas flowwithin a tube;

FIGS. 8A-B illustrate an exemplary embodiment of a device for diffusinga high NO source concentration, low volume gas flow and a high volumegas flow;

FIGS. 8C-D illustrate another exemplary embodiment of a device fordiffusing a high NO source concentration, low volume gas flow and a highvolume gas flow;

FIG. 9A illustrates an exemplary embodiment of a tapered section havinga funnel shape;

FIG. 9B illustrates an exemplary embodiment of a tapered section havinga cone shape;

FIG. 9C illustrates an exemplary embodiment of a tapered section havinga bell shape;

FIG. 10 illustrates an exemplary embodiment of a bi-directional taperedsection;

FIG. 11 illustrates an exemplary tapered section depicting a convexcontour of an inside surface of a tapered section wall;

FIG. 12 illustrates an exemplary embodiment of a second gas passingthrough an injection channel into a first gas passing through a taperedsection;

FIG. 13 illustrates an exemplary embodiment of a diffusing deviceinserted into a ventilator circuit;

FIG. 14 shows a comparison of the NO₂ generated during mechanicalventilation using an exemplary diffuser described herein and aconventional low source concentration injector module;

FIGS. 15A-F show a comparison of the NO₂ generated under steady stateFGF flow conditions within smooth bore tubing using an exemplarydiffuser described herein, an exemplary accelerator as described herein,and a conventional low source concentration injector module;

FIG. 16 shows the reduction of the NO₂ generated by heating an exemplaryventilator breathing circuit;

FIG. 17 shows the NO₂ generated in the initial region with various NOsource cylinder concentrations ranging from 800 ppm to 9760 ppm with agas velocity ratio (FGF:NO) of approximately 1:1;

FIGS. 18A-D show the NO₂ generated in the initial region with various NOsource cylinder concentrations ranging from 800 ppm to 9760 ppm with avarying gas velocity ratio (FGF:NO) and a set dose of 10 ppm NO;

FIG. 19 shows the NO₂ generated in the initial region with a 4880 ppm NOsource cylinder concentration and a set dose of 40 ppm, with a varyinggas velocity ratio (FGF:NO);

FIGS. 20A-B show the NO₂ generated in the initial region with various NOsource cylinder concentrations ranging from 800 ppm to 9760 ppm with avarying gas velocity ratio (FGF:NO) and a set dose of 10 ppm NO;

FIG. 21 shows the NO₂ generated in the initial region with a 4880 ppm NOsource cylinder concentration and a set dose of 40 ppm, with a varyinggas velocity ratio (FGF:NO); and NO₂ generated during homogeneous phaseof 40 ppm equal to set dose; and

FIGS. 22A-B show the NO₂ generated in ppm and as a percentage of the setdose with simulation of expiratory time period change relative toinspiratory time period with higher flows.

DETAILED DESCRIPTION

The present invention, generally speaking, is directed to systems andmethods of injecting NO into fresh gas flow in the inspiratory limb of aventilator breathing circuit such that NO₂ generation is minimized. Thepresent invention takes advantage of previously unknown factors whichapplicant surprisingly found affect NO₂ generation. More specifically,systems and methods of the present invention can be used to deliver NOfrom a source of high concentration NO (e.g., 5000 ppm NO source) intofresh gas flow in the inspiratory limb of a ventilator breathing circuitsuch that NO₂ generation is substantially minimized and/or the NO₂generated is within a desired range (e.g., less than 1 ppm NO₂ deliveredto the patient, the same or less NO₂ as generated by substantially lowerconcentration NO sources using conventional injector modules, etc.) byfactoring in variables such as, but not limited to, location ofinjection of NO into fresh gas flow, fresh gas flow velocity, NO flowvelocity, and/or ratio of impinging velocity of NO and fresh gas flow,to name a few.

Further, systems and methods of the present invention can be used with aventilator breathing circuit by not substantially causing pressure drop,for example less than 1.5 cm H₂O at 60 SLPM, minimizing flow profilechanges, minimizing the increase in the compressible volume of fresh gasflow, and/or enabling for patient spontaneous breathing in theventilator breathing circuit. Further still, systems and methods of thepresent invention can be used immediately downstream from flow sensorsthat require the fresh gas flow be laminar and/or can be usedimmediately upstream from at least one gas sampling line.

“Compressible volume” means the volume of a conduit and all componentsin fluid communication with and in line with the flow path of theconduit. For example, the compressible volume of breathing circuit isthe volume of the breathing circuit and all of the components within it(e.g. humidifier, injector module, sample T's).

As used herein, “diffusion”, “diffusing” and related terms refer to theoverall transport of molecules of one gas (e.g. NO) into and throughouta stream of another gas (e.g. oxygen-enriched air). The use of the terms“diffusion”, “diffusing” and related terms does not exclude thecontribution of bulk fluid motion or other transport phenomena to themixing and homogenization of two or more gas streams.

As noted above, prior to applicant's research, it was believed that NO₂formation was predicated on the concentration of NO and O₂ (e.g.,parts-per-million of NO, percent of O₂ (otherwise known as FiO₂)), aswell as the distance/dwell time between gas mixing and the patient.Following this belief, delivery of NO from a high concentration source(e.g., 5000 ppm, 10,000 ppm NO cylinder) would result in substantiallyhigh levels of NO₂. For example, a 4880 ppm NO cylinder concentrationreduced down to a set dose of 10 ppm is a turn down ratio of 488:1,whereas a 800 ppm cylinder concentration reduced down to a 10 ppm setdose has a turn down ratio of 80:1, theoretically NO₂ is generated at arate approximately 37 times greater with a 4880 ppm NO supply than witha 800 ppm NO supply cylinder for a dose of 10 ppm. Without a means ofovercoming this problem, high concentrations sources of NO cannot beused for INO therapy as this would result in delivery of undesirablyhigh levels of NO₂ to a patient, and many benefits associated with usinghigh concentration sources of NO for INO therapy (e.g., smaller NOsupply cylinders, increased portability of INO therapy devices, smallervolumes of NO-containing gas (e.g., nitrogen and NO gas blends) in thebreathing circuit, reduced inspired oxygen dilution due to smallerinjected NO-containing gas volumes, etc.) would be unrealized.

In exemplary embodiments, using a higher concentration source gas canreduce a portion of the NO₂ delivered to a patient. For example, thehigher the NO concentration of the source gas, the smaller the volume ofsource gas required to be delivered to obtain the desired set NO dose.Even with the same NO₂ concentration in the source gas (e.g. the sameNO₂ concentration in a gas cylinder), by using this lower volume ofsource gas, less volume of NO₂ from the source gas would be deliveredand hence the patient receives less NO₂ from the NO source (e.g.cylinder).

In light of at least these unrealized benefits, applicant conductedextensive research and testing into NO₂ generation when injecting NOinto the inspiratory limb of a ventilator breathing circuit.

From this research and testing, it was surprisingly found that NO₂formation was greater during the expiratory phase of ventilation, inwhich fresh gas flow in the inspiratory limb of a ventilator issubstantially slower, laminar (non-turbulent) than during theinspiratory non-laminar (turbulent) phase of ventilation. With thisknowledge, further research and testing was conducted to determine therelationship between the NO₂ output and variables such as the impingingvelocity of the NO-containing gas, the flow rate of the FGF, and the NOdose. In each of these experiments, the fresh gas was oxygen-enriched(e.g. 60% O₂/air), the NO₂ concentration was measured at a distancebeyond the NO injection point (e.g. 1,000 mm), and the NO sourceconcentration was either a low concentration (e.g. 800 ppm NO) or a highconcentration (e.g. 4880 ppm NO). The NO was injected and the gases weremixed using a conventional injector module. The results of this testingare shown in Tables 1-2 and FIGS. 1A-F.

TABLE 1 NO₂ Generated with Low Concentration NO Source NO₂ Delivery (ppmNO₂) NO Dose 5 10 20 40 80 FGF 0.5 0.17 0.2 0.39 0.95 2.3 Flow 2 0.0890.13 0.26 0.56 1.7 Rate 8 0.067 0.101 0.22 0.47 1.5 (SLPM) 15 0.065 0.080.16 0.48 1.4 30 0.065 0.096 0.2 0.44 1.4 60 0.063 0.081 0.21 0.46 1.3

TABLE 2 NO₂ Generated with High Concentration NO Source NO₂ Delivery(ppm NO₂) NO Dose 5 10 20 40 80 FGF 0.5 1.9 2.6 3.4 2.9 3.3 Flow 2 0.80.63 0.36 0.57 1.7 Rate 8 0.088 0.089 0.14 0.41 1.2 (SLPM) 15 0.0730.075 0.11 0.34 1.2 30 0.047 0.089 0.13 0.34 1.2 60 0.032 0.055 0.140.34 1.2

FIGS. 1A and 1B show that the impinging velocity of NO with fresh gasflow in the breathing circuit can substantially impact the amount of NO₂generated. Also, as can be seen by comparing FIG. 1A (low concentration)and FIG. 1B (high concentration), increasing the NO concentrationgenerally increased the amount of NO₂ produced.

FIGS. 1C-1F show the respective amounts of NO₂ generated for differentset NO dosages when the NO is injected into the FGF having differentflow rates. As can be seen by comparing FIG. 1C (low concentration) andFIG. 1D (high concentration), increasing the NO concentration generallyincreased the amount of NO₂ produced, particularly at the lower flowrates of FGF. This is also shown by comparing FIG. 1E (lowconcentration) and FIG. 1F (high concentration), as the NO₂ output curvefor 0.5 SLPM was drastically different between the low NO sourceconcentration and the high NO source concentration.

Although the above is beneficial in understanding NO₂ generation, itsubstantially complicates minimizing NO₂ generation when NO (e.g., froma high concentration NO source) is being injected into the inspiratorylimb of the ventilator breathing circuit. For example, the fresh gasflow velocity can vary (e.g., the fresh gas flow rate can vary over thecourse of the patient breathing cycle, etc.); the NO velocity injectedinto the fresh gas flow can vary (e.g., the NO flow rate can varydepending on the pressure in the NO delivery line, the dimensions of theNO injection port at the diffusing device, the dimensions of the NOdelivery conduit in the NO delivery system, to name a few); andratio-metric delivery, as may be required for INO therapy, for example,to achieve a constant inspired NO concentration, can require varying theNO delivered in proportion to the fresh gas flow. During the expiratoryphase some ventilators use low bias flows (0.5 SLPM) and have slower FGFin a ventilator breathing circuit, which may generate more NO₂ thanduring the inspiratory phase (faster FGF in the ventilator breathingcircuit). For example, the data above shows that 10 to 20 times more NO₂may be generated with 4880 ppm NO than with 800 ppm NO at low FGFassociated with ventilator exhalation bias flows over the same timeperiod, where insufficient diffusing may occur with a conventionalinjector module.

Accordingly, in exemplary embodiments, a diffusing device can bedesigned to minimize NO₂ generation by controlling the impingingvelocity of the NO and fresh gas flow and the location of injection ofthe NO into the FGF. In various embodiments, the velocity of the NO flowstream may be high enough relative to the FGF at the location the NO isinjected to minimize the NO₂ generated. Without being bound by theory,it is thought the NO flow stream may penetrate the FGF streamperpendicularly and with proportional velocities. With very low NOvelocity relative to FGF velocity, without being bound by theory, it isbelieved the NO stays at the outer wall of the FGF stream resulting inpoor mixing. Conversely, if only the NO velocity is high and the FGF isnot, the mixing time can also be extended resulting in high NO₂.

While not wishing to be bound by any particular theory, it is believedthat the initial contact diffusion rate of the two mixing gas streamsmay be primarily controlled by the molecular kinetic energy. In such agas impingement mixing process, the dissipative exchange from gasmomentum can provide direct acting mixing. This rapid diffusion can takeplace immediately in the vicinity of the nozzle outlet, or directly atthe gas impingement point. The molecular kinetic energy is defined as ½times the molar mass times the square of the velocity, and thus thevelocity is inversely proportional to the square root of the molar mass.Equivalent volumes of different gases contain the same number ofparticles, and the number of moles per liter at a given temperature andpressure is constant. This indicates that the density of gas is directlyproportional to its molar mass. Accordingly, this indicates the samemixing energy (i.e. same kinetic energy) would exist at approximatelyequal velocities or a ratio of 1:1, due to the similar molecular weightsof NO, N₂, air and O₂, which all range from 28 to 32 grams per mole.However, given the slight molecular weight imbalance between air/O₂mixtures and NO/N₂ mixtures, the greatest diffusion from the dissipativeenergy exchange can be at velocity ratios less than 1:1 (FGF:NO), suchas 0.85:1, 0.9:1 or 0.95:1, depending on the relative proportions of N₂,NO, O₂ and air.

In various embodiments, the velocity of the two gas streams may beproportional to each other in order to minimize the NO₂ generated. TheNO velocity can be controlled by changing the dimensions of the NOinjection port, for example, as other factors (e.g., pressure in the NOdelivery line, dimensions of the NO injection channel, etc.) may befixed. It will be appreciated that any means for controlling the NOvelocity can be used. However, controlling the fresh gas flow velocitycan be substantially challenging as the velocity of the fresh gas flowis typically controlled by the ventilator. Further, as noted above, thevelocity of the fresh gas flow during the expiratory phase can besubstantially slow. In at least some instances, the impinging velocityof the fresh gas flow during at least the expiratory phase can be tooslow to minimize NO₂ generation. Accordingly, in exemplary embodiments,the diffusing device can include at least one accelerator capable ofaccelerating the fresh gas flow to a desired impinging velocity, forexample, that may be directed to a point of intersection with theNO-containing gas.

In one or more embodiments, the orifice diameter at the NO gasimpingement point to the fresh gas flow tube can be sized appropriatelyto maintain a fixed aspect ratio outlet area between the diffusingmodule 100 tube diameter (i.e. the FGF tube diameter) to the NO nozzleoutlet diameter area (i.e. the injection port orifice diameter). Thisratio in tube outlet area can be proportional to the NO cylinderconcentration over the NO set dose. For example, for an 800 ppm cylinderconcentration at a set dose of 20 ppm, a 40 to 1 turn down ratio existsin NO flow rate. In order to maintain a 1:1 impinging gas velocityrelationship, an injector module flow tube area to injection nozzleoutlet area may be sized at 40:1 at the lowest expected fresh gas flowrate (e.g., 0.5 SLPM). As another example, for a 4880 ppm cylinderconcentration at a set dose of 10 ppm, a 488 to 1 turn down ratio existsin NO flow rate. In order to maintain a 1:1 impinging gas velocityrelationship, an injector module tube area to injection nozzle outletarea may be sized at 488:1

In one or more embodiments, the dimensions of the injection channel andinjection port may be adjusted so the ratio of NO velocity to FGFvelocity is less than about 2:1, such as about 1.5:1, 1:1, 0.95:1,0.9:1, 0.85:1, 0.8:1, 0.7:1, 0.6: 0.5:1, 0.4:1, 0.3:1, 0.2:1, 0.1:1 or0.05:1.

In exemplary embodiments, at least one accelerator can be any device orcomponent capable of accelerating all or a portion of the fresh gasflow. For example, the accelerator can be a conical structure with atapered surface, a tapered section, bi-directional conical structure,and/or any shapes or surfaces capable of accelerating fresh gas flow.Other examples include structures with surfaces similar to a wing, asgas flowing over the top of a wing (curved surface) has a fastervelocity than the gas flowing underneath the bottom of the wing(relatively flat surface). These accelerator structures are onlyexemplary, and other structures capable of accelerating at least someportion of a gas flow are also within the scope of this invention.

Notably, when injecting NO into fresh gas flow, the device'sconfiguration and dimensions may be adjusted to reduce the source NOconcentration as quickly as possible. In various embodiments, mixingfeatures may be added to the device downstream of the NO injectionpoint. In various embodiments, mixing can be thought of in 2 phases. Thefirst phase where the majority of NO₂ may be generated is the time fromNO injection to when the NO concentration reaches the set dose (e.g., ahomogeneous state equal to the set dose). The second phase of NO₂generation is due to the residence time in the inspiratory limb at setdose. A majority of NO₂ may be generated at, or near, the first point ofcontact between the NO and fresh gas flow (e.g., O₂). These two phasesof NO generation can be seen in FIG. 1G, which shows the NO₂concentration at various points downstream from the point of injection.As can be seen from FIG. 1G, the majority of the NO₂ is generated soonafter the NO is injected (Phase 1), with only a small portion of the NO₂being generated after the initial injection and mixing of the NO (Phase2). This majority of the NO₂ being generated during the first phasefollows the above NO₂ generation kinetics as the first phase of NOinjection the local NO concentration is highest (e.g., as the NO has notyet diffused into the fresh gas flow to provide the homogenous set NOdose). By way of example, when injecting 5000 ppm NO into the breathingcircuit, at the point of injection the NO concentration is highest(e.g., approximately 5000 ppm NO) as the NO has not yet diffused withthe fresh gas flow. After this point of injection, the injected NO andthe fresh gas flow diffuse together causing the NO concentration todecrease to a lower concentration (e.g., from 5000 ppm NO to a desireddose of 20 ppm NO).

Accordingly, one approach for rapidly mixing the NO and FGF is the useof a mixing device placed immediately downstream or close to the pointof NO injection to ensure that the combined gas stream has a homogenousNO concentration as soon as possible. For example, a plurality ofblades, plates and/or fins can be placed downstream of the NO injectionpoint to ensure prompt mixing of the two gas streams. 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15 or more blades, plates and/or fins canbe used. FIGS. 2A-C provide various views of an exemplary configurationof a mixing device having four blades. FIGS. 3A-C provide various viewsof an exemplary configuration of a mixing device having three angledfins. FIGS. 4A-C provide various views of an exemplary configuration ofa mixing device having eight plates. FIGS. 5A-C provide various views ofan exemplary configuration of a mixing device having four curved blades.FIGS. 6A-C provide various views of an exemplary configuration of amixing device having four curved blades and an injection channel at atapered section.

When a plurality of blades, plates and/or fins are used in a mixingdevice, the blades, plates and/or fins can be placed in parallel at thesame distance downstream from the NO injection point and/or may beplaced in series at various distances downstream from the NO injectionpoint. For example, each blade, plate or fin may be placed 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90 or 100 cmdownstream from the NO injection point.

The presence of a mixing device can also be used to shorten the distancebetween the NO injection point and one or more sampling points formonitoring the composition of the combined gas, such as the O₂, NO andNO₂ concentrations. For example, the first sampling point can be located1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80,90 or 100 cm downstream from mixing device. Furthermore, a plurality ofsampling points may be used, such as sampling points located at variousdistances from the NO injection point. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,15, 20, 25, 30 or more sampling points may be used. The distance betweensampling points can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or 30cm. The plurality of sampling points can be used to separately analyzethe combined gas stream as a function of length down the breathingcircuit, or two or more sampling can be combined to provide an averagefor the composition of the gas.

Furthermore, the location of the point of injection of NO into the freshgas flow can influence the reduction in NO₂ generation. In exemplaryembodiments, the NO injection point can be located where the residencetime of the initial high concentration is minimized and/or initial highconcentration NO is rapidly dispersed. For example the point ofinjection of NO (e.g., high concentration NO, 5000 ppm NO) may belocated at the center of the annular body or as part of the taperedsection, to reduce the amount of time that the NO remains at the initialhigh concentration. Accordingly, the point of NO injection can belocated where the NO will be intermixed quickly with the fresh gas flowthereby minimizing the residence time of the high concentration NO andin turn reducing the NO₂ generated. While not wishing to be bound by anyparticular theory, it is believed that injecting the NO at a point inwhich the fresh gas flow has a high velocity will generate less NO₂ thanother traditional techniques of injecting NO at the edge (i.e. wall) ofthe tube where fresh gas flow will have a low velocity.

FIG. 7 illustrates an exemplary velocity distribution of a gas flowthrough a tube. As can be seen from FIG. 7, the gas flow has the lowestvelocity closest to the edge boundary (e.g. wall of the tube) and hasthe highest velocity farthest from the edge boundary. Accordingly, insome embodiments the NO is injected at a distance from the edge boundarywhere the gas velocity is higher than the gas velocity at or close tothe edge boundary.

In exemplary embodiments, to reduce NO₂ generation, the point ofinjection of NO into fresh gas flow can be located where the fresh gasflow is accelerated to the desired velocity. The accelerator may act toincrease the fresh gas flow velocity from an inlet end to the outletend, and the injection port located a distance from the inlet at whichthe fresh gas flow has increased to an intended velocity. The increasein velocity may be created by conversion of the gas's potential energyto kinetic energy. By way of example, the velocity may be increased bythe reducing cross section of the tapered section, as the gas flows froma region of higher pressure to a region of lower pressure. The gasvelocity being proportional to the change in cross-sectional area andchange in gas density. Of course other techniques for increasing thevelocity are envisioned.

Further complicating any potential solutions for minimizing NO₂generation when injecting NO into the ventilator breathing circuit,ventilators require that any element (e.g., injector module, NO₂minimization device, etc.) used with the ventilator breathing circuitnot cause a substantial change to the ventilator inspiratory flowprofile (by way of increased resistance to flow or increasedcompressible volume). Generally speaking, the allowable pressure dropacross the entire breathing circuit can be 6 cm H₂O at 30 SLPM foradults, 6 cm H₂O at 15 SLPM for pediatrics and 6 cm H₂O at 2.5 SLPM forneonates inclusive of ventilator outlet resistance. In light of this,the allowable pressure drop across the diffuser should be minimized. Forexample, current INOmax DS Injector Module is rated at 1.5 cm H₂O at 60SLPM. Accordingly, systems and methods of the present invention minimizeNO₂ without affecting ventilator performance and/or causing substantialpressure drops, flow profile changes, and introducing substantialcompressible volumes, for example, that may affect patient ventilationgas exchange.

Accordingly, in exemplary embodiments, the diffusing device can beconfigured and dimensioned so that at least the accelerator increase thefresh gas flow impinging velocity at the lowest expected fresh gas flowrate while not causing a substantial pressure drop in the highest peakfresh gas flow, not cause substantial changes to the inspiratory freshgas flow's flow profile, and not create a substantial compressiblevolume in the breathing circuit. For example, the mouth and throatdiameter may be selected to increase FGF velocity while minimizing delayin pressure changes and gas flow to a patient. To minimize changes topressure, flow, and compressible volume the diffusing device can includea region for fresh gas flow to bypass the accelerator. For example, thediffuser can include a bypass gap which may be located about theperiphery of the diffuser and/or accelerator.

After using the techniques disclosed herein to minimize NO₂ generationin the first phase (e.g., rapidly diffusing the NO and fresh gas flow atthe point of injection, etc.), the NO may continue to traverse theremaining region of the breathing circuit at, or very close to, thedesired set dose (e.g., 1 to 80 ppm NO). As this NO dose, or very closeto the desired set dose, traverses the remaining region of the breathingcircuit NO₂ may be generated (second phase); however, as describedabove, using the techniques disclosed herein, the majority of NO₂ thatwould have been produced will be substantially minimized therebysubstantially reducing the total amount of NO₂ generated (e.g.,immediate NO₂ generated and latent NO₂ generation).

To further mitigate NO₂ generation, NO may be introduced (e.g., in theventilator breathing circuit) as close to the patient as technicallyfeasible to reduce the contact time by reducing the time the NO and O₂are in transit together, thus partly reducing NO₂ formation. NO₂conversion time is the elapsed time NO and oxygen resides in combinationprior to reaching the patient. NO₂ conversion time is therefore afunction of ventilator flow rates (inspiratory and expiratory),ventilator I:E ratio, and breathing circuit volume from the point of NOinjection to the patient airway end.

However, as explained above, in exemplary embodiments the downstream NO₂generation (i.e. Phase 2) is much less than the NO₂ generation uponinjection (Phase 1). Accordingly, in some embodiments the NO-containinggas is injected at a position that is significantly upstream from thepatient, such as several feet from the patient, yet the NO₂ can be at anacceptable level (e.g. less than 1 ppm). Exemplary NO injection pointsinclude those at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 feet upstreamfrom the patient. Such locations can be upstream of a patient “Y” piece,upstream of a humidifier, upstream of a nebulizer or other locationsupstream from the patient in the ventilator breathing circuit.

In various embodiments, the second gas stream may be injected at anangle in the range of about 60° to about 120°, or at an angle in therange of about 75° to about 105°, or about 80° to about 100°, or about85° to about 95°, or at about 90° to the axis of the first gas stream.

An aspect of the present invention relates to an injection device forinjecting a high concentration gas into a transverse gas stream.

In one or more embodiments, the device comprises an injection port thatinjects the second gas stream perpendicularly into the first gas stream.

In various embodiments, a high concentration NO-containing gas may be inthe range of greater than 800 ppm NO to about 5000 ppm NO, or about 2000ppm NO to about 4880 ppm NO, or at about 4880 ppm NO. Exemplary lowerlimits include about 800 ppm, about 1,000 ppm, about 1,200 ppm, about1,400 ppm, about 1,600 ppm, about 1,800 ppm, about 2,000 ppm, about2,200 ppm, about 2,400 ppm, about 2,600 ppm, about 2,800 ppm, about3,000 ppm, about 3,200 ppm, about 3,400 ppm, about 3,600 ppm, about3,800 ppm, about 4,000 ppm, about 4,200 ppm, about 4,400 ppm, about4,600 ppm, and about 4,800 ppm. Exemplary upper limits include about10,000 pm, about 9,000 ppm, about 8,000 ppm, about 7,000 ppm, about6,500 ppm, about 6,000 ppm, about 5,500 ppm, about 5,200 ppm, about5,000 ppm and about 4,900 ppm. The high concentration NO-containing gasmay be contained in a pressurized cylinder at a pressure in the range ofabout 200 psig and about 3000 psig, or in the range of about 2000 psigand about 2400 psig, or about 2200 psig and about 2400 psig. Of courseother sources of high concentration NO are envisioned.

FIGS. 8A-B illustrate an exemplary device for diffusing a highconcentration low volume gas flow and a high volume gas flow using thetechniques disclosed above.

In one or more embodiments, the diffusing device 100 comprises a body110 that may be an annular body formed by a cylinder having a wall 115and a hollow (also referred to as open), internal region 118. The body110 may be configured and dimensioned to connect to tubing in aventilator breathing circuit (e.g., 10, 15 and 22 mm), fit intoventilator tubing, or have ventilator tubing fitted into the body. Invarious embodiments, the inlet end of the device comprises a maleconnection configured and dimensioned to join to a ventilator tube, andthe outlet end comprises a female connection configured and dimensionedto join to a ventilator tube or humidifier chamber inlet. In anon-limiting example, the inlet end of the device comprises a 22 mm(O.D.) male connection, and the outlet end comprises a 22 mm (I.D.)female connection. In addition, in various embodiments the diffusingdevice 100 can be a component or part of an injector module whichcouples to a ventilator breathing circuit or component such ashumidifier chamber, as is known in the art.

In one or more embodiments, the diffusing device 100 comprises a body110 that may be rectangular, cubic or other geometric shapes that areconfigured and dimensioned to connect to tubing in a ventilatorbreathing circuit (e.g., 10, 15 and 22 mm), and having a hollow internalregion. For convenience, in embodiments where the body comprises acylindrical wall, the body is referred to as an annular body in thespecification.

In one or more embodiments, an annular body 110 may have an outsidediameter ‘A’ at an inlet end and/or an outlet end. The outside diameter‘A’ may be in the range of about 10 mm (0.394 in.) to about 25 mm (1.0in.), or about 22 mm (0.866 in.), where the ventilator tubing may befitted around the outside of the inlet end OD and inside the outlet endID. In various embodiments, a ventilator tube may be connected to aninlet end and/or outlet end of a diffusing device utilizing afriction-fit connection, as would be known in the art. In variousembodiments, the OD at the inlet end may be the same or different fromthe OD of the outlet end.

In one or more embodiments, the annular body may have an inside diameter‘B’ at an outlet end and/or an inlet end. The inside diameter ‘B’ may bein the range of about 10 mm (0.394 in.) to about 25 mm (1.0 in.), orabout 22 mm (0.866 in.), where the ventilator tubing may be fitted intothe inside of the inlet end ID. In various embodiments, a ventilatortube may be connected to an inlet end and/or outlet end of a diffusingdevice utilizing a friction-fit connection, as would be known in theart. In various embodiments, the ID at the inlet end may be the same ordifferent from the ID of the outlet end.

In one or more embodiments, gas(es) may enter the inlet end of thediffusing device 100 and exit the outlet end of the diffusing device,where the gas(es) may comprise a mixture of breathable gases. In variousembodiments, the breathable gases may comprise air, or air andadditional oxygen.

In various embodiments, the wall thickness ‘C’ of a cylindrical wall 115may be in the range of about 1 mm (0.040 in.) to about 3.175 mm (0.125in.), or in the range of about 1 mm (0.040 in.) to about 2 mm (0.079in.), or in the range of about 1.588 mm (0.0625 in.) to about 2.388 mm(0.094 in.).

In one or more embodiments, the diffusing device may have a length ‘D’in the range of about 6.35 mm (0.25 in.) to about 41.3 mm (1.625 in.),or in the range of about 22.225 mm (0.875 in.) to about 41.275 mm (1.625in.), or in the range of about 25.4 mm (1.00 in.) to about 38.1 mm (1.50in.).

In one or more embodiments, a nipple 190 for attaching a delivery tubeto the diffusing device may protrude from the outer surface of thecylindrical wall 115. In various embodiments, the nipple may have adiameter ‘M’ 4.5 mm diameter (0.177″) and protrude from the outersurface of the cylindrical wall 115 a height ‘N’ 8.7 mm (0.34 in.). Invarious embodiments, the nipple may comprise hose barbs for affixing adelivery tube.

In one or more embodiments, the device further comprises a projection195 extending from the inner surface of the cylindrical wall 115. Invarious embodiments, the projection 195 may extend a radial distance ‘P’into the hollow internal region 118. In various embodiments, theprojection 195 may extend up to or close to the center of the hollowinternal region 118, which would be half of the ID of the wall 115. Invarious embodiments, distance ‘P’ is slightly under half the ID so thatthe NO-containing gas will project out forward from the nozzle orificeto the middle, where the FGF gas velocity is higher than at the innersurface of the cylindrical wall. Accordingly, in various embodiments,the difference between ‘P’ and ‘B’/2 is in the range of from about 0.1mm to about 5 mm, or about 0.5 mm to about 3 mm. In exemplaryembodiments, the difference between ‘P’ and ‘B’/2 is about 1.5 mm, i.e.the projection 195 ends about 1.5 mm from the center of the hollowinternal region 118. Exemplary differences between ‘P’ and ‘B’/2 canhave a lower limit of about 0.1 mm, about 0.2 mm, about 0.3 mm, about0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about0.9 mm, about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 and about 1.4mm, and exemplary upper limits can be about 5 mm, about 4.5 mm, about 4mm, about 3.5 mm, about 3 mm, about 2.5 mm, about 2.4 mm, about 2.3 mm,about 2.2 mm, about 2.1 mm, about 2 mm, about 1.9 mm, about 1.8 mm,about 1.7 mm and about 1.6 mm.

In some embodiments, ‘P’ is provided as a certain percentage of ‘B’,such as about 50%, about 49%, about 48%, about 47%, about 46%, about45%, about 40%, about 40%, about 35%, about 30%, about 25%, about 20%,about 15%, about 10% or about 5% of ‘B’. In exemplary embodiments, ‘P’is between about 40% and about 45% of ‘B’.

In one or more embodiments, the dimensions ‘B’, ‘P’, ‘L’, etc. may beselected to achieve desired relationships between the dimensions and/ordesired relationships between gas properties under certain conditions.For example, ‘B’ and ‘L’ may be selected such that for a given sourcegas concentration and a given desired NO dose (e.g. 20 ppm), the gasvelocity at the lowest expected FGF will be approximately equal to thegas velocity of the NO-containing gas. As another example, ‘B’ and ‘L’may be selected such that for a given source gas concentration, the gasvelocity of the FGF will be similar to the gas velocity of theNO-containing gas over a range of desired NO doses (e.g. 5 ppm to 80ppm). As another example, ‘B’ and ‘P’ may be selected such that theNO-containing gas projects out forward from the nozzle orifice to adistance from the inner surface of the cylindrical wall, such as at ornear center of the hollow internal region 118. As a further example, ‘B’and ‘P’ may be selected such that the NO-containing gas projects outforward from the nozzle orifice to a portion of the FGF having a certainpercentage of the peak velocity of the FGF, such as 99%, 98%, 95%, 90%,85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20% or10% of the peak velocity of the FGF.

In various embodiments, an injection channel 180 leading to an injectionport 185 may be formed in the nipple, where the injection channel 180has an inside diameter of ‘L’. In various embodiments, the insidediameter ‘L’ may be in the range of about 0.8 mm (0.03125 in.) to about2.4 mm (0.094 in.), or about 1.6 mm (0.0625 in.). Exemplary lower limitsinclude about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about0.9 mm, about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4mm, about 1.5 mm and about 1.6 mm. Exemplary upper limits include about4.75 mm, about 4.5 mm, about 4 mm, about 3.5 mm, about 3 mm, about 2.5mm, about 2.4 mm, about 2.29 mm, about 2.2 mm, about 2.1 mm, about 2 mm,about 1.9 mm, about 1.8 mm, about 1.7 mm and about 1.6 mm. The injectionchannel provides a flow path for delivery of a gas (e.g., NO) to thehollow internal region 118 of the diffusing device 100.

In one or more embodiments, the diffusing device 100 does not comprise anipple 190 projecting from the body 110, but has a female connector intowhich a delivery tube may be plugged, where the female connector allowsthe delivery tube to be connected to and in fluid communication with theinjection channel 180. In various embodiments, the ID of the deliverytube and the ID of the injection channel are the same and/or have auniform cross-sectional area.

In one or more embodiments, the injection port 185 may be an orificeallowing a gas flowing through the injection channel 180 to enter thehollow internal region 118 at an intended rate and/or velocity. Invarious embodiments, the injection port may be an opening of fixeddimension that may be the same or different from the diameter of theinjection channel, which provides an intended flow velocity related tothe flow rate. In various embodiments, more than one injection port 185can be used, such as by having multiple injection ports 185 along thelength of the projection 195 and/or by having multiple projections 195,with each projection 195 having one or multiple injection ports 185. Asset forth above, the injection ports may inject the NO-containing gasinto a portion of the FGF that is a distance from the edge boundary sothat the NO-containing gas is injected into FGF having a high velocity,not a portion of the FGF having zero or low velocity. In someembodiments, when more than one injection ports 185 are used, thediameters of the injection ports 185 have smaller diameters than wouldbe used for a single injection port 185 to ensure that the velocity ofthe NO-containing gas is not reduced and is maintained in proportion toFGF velocity.

In some embodiments utilizing multiple injection ports 185, only one orsome of the injection ports 185 may be used at a time, with selectiondependent on the set dose of NO. For example, the multiple injectionports 185 can have varying orifice diameters, with a smaller orificediameter being used for lower set doses of NO and a larger orificediameter being used for higher set doses of NO. In this way, the ratioof the velocities of the NO-containing gas and the FGF can be maintainedat a constant ratio, even with different set doses of NO. In someembodiments, more ports 185 are used at higher set doses of NO and lessinjection ports 185 are used at lowers set doses of NO, to tailor thevelocities of the NO-containing gas and the FGF to the desired ratio. Inother embodiments, all of the multiple injection ports 185 may be usedconcurrently. In various embodiments, multiple injection ports 185 maybe multiple proportional control valves as part of the injector module.

In one or more embodiments, a valve (not shown) and/or variable orificecan be in fluid communication with the injection port 185 and/or can belocated at the injection port 185. The proportional valve and/orvariable orifice can be adjusted to control the velocity of gas beinginjected from the injection channel 180 into the hollow internal region118. In various embodiments, the size of a valve orifice and/or variableorifice and velocity of gas being injected through the injection port185 may be adjusted in relation to the FGF velocity, where the valve andgas velocity may be controlled through a feedback loop. In variousembodiments, the feedback loop may comprise a flow sensor capable ofmeasuring fresh gas flow in the breathing circuit, where the flow sensormay be in electrical communication with a control module that controlsthe dosage of NO fed into the diffusing module 100 through the injectionchannel 180 and the valve and/or variable orifice by adjusting the valveand/or variable orifice. In one or more embodiments, the diffuser andflow sensor capable of measuring fresh gas flow are incorporated into asingle piece, such as being integral to an injector module.

In one or more embodiments, the diffusing module 100 comprises aproportional control valve, an NO flow sensor and a FGF flow sensor formeasuring the fresh gas flow in the breathing circuit and delivering aflow of NO-containing gas that is proportional to the FGF to provide thedesired set dose of NO. In such embodiments, the proportional controlvalve and/or flow sensor can be eliminated from the control module. Sucha configuration can eliminate a compressed gas volume between thecontrol module and the diffuser, as the proportional valve within thediffusing module 100 is used as the primary valve for regulating theflow of the NO-containing gas into the breathing circuit. While notwishing to be bound by any particular theory, it is believed that havingboth a proportional valve in the diffusing module 100 and a proportionalvalve in the control module can result in compressed gas being storedwithin the injection channel and NO delivery tube at the end of eachinspiratory cycle, and that this compressed gas may then decompress,allowing a quantity of NO-containing gas to enter the breathing circuitand causing over delivery of NO. This potential problem can be magnifiedwith high concentration NO, due to the decreased delivery volume.Accordingly, substituting a proportional control valve in the diffusingmodule 100 for the proportional control valve in the control module canreduce or eliminate the impact of this potential problem.

In one or more embodiments, the NO-containing gas is injected into theFGF as a plurality of pulses from one or more injection ports 185. Theplurality of pulses can be used to provide a higher velocity of theNO-containing gas than if the flow of the NO-containing gas wasconstant. By providing pulses (e.g. NO flow OFF-ON-OFF-ON), a higherinstantaneous NO volumetric flow rate can be provided with acorresponding increase in instantaneous NO velocity, without providing ahigher average volumetric flow rate than needed to provide the desiredNO concentration in the combined gas stream. As an example, if thesystem was to detect low FGF bias flow (e.g. 0.5 SLPM), the NO can bedelivered as a plurality of high-velocity pulses to maintain the correctquantity of NO-containing gas volume during this phase. In this way, theNO delivery system can utilize pulse width modulation of NO flow (e.g.during expiratory bias flow) to maintain a higher gas velocity of NO inproportion to FGF gas velocity, while maintaining the desired average NOflow rate or set dose concentration.

During expiratory phase only delivery of pulsatile high peak flow toincrease the NO exit velocity. In order to maintain the correct quantityof gas volume during this phase. The pulsatile flow would beOff-ON-Off-On to meet the average flow rate required to meet set Dose.Pulse width modulation of NO flow.

Aspects of the invention also relate to method of diffusing a highconcentration gas into a transverse gas stream comprising passing atleast a portion of a first gas longitudinally through a hollow internalregion of a body having an inner surface surrounding the hollow internalregion, and passing a second gas stream through an injection channel toan injection port projecting into the hollow internal region of thebody, wherein the second gas stream enters and at least partiallydiffuses with the first gas stream within the hollow internal region.

FIGS. 8C-D illustrate another exemplary device for diffusing a highconcentration low volume gas flow and a high volume gas flow using thetechniques disclosed above. Of course, other configurations capable ofdiffusing a high concentration low volume gas flow and a high volume gasflow using the above techniques are envisioned. The dimensions areexemplary for a 22 mm nominal diffuser for use with adult breathingcircuits/fittings. It should be noted that the non-limiting examples ofdimensions and/or configurations are intended for standard adultbreathing circuits, and the dimensions and proportions of the device maybe adjusted for applications involving standard neonate breathingcircuits, standard pediatric breathing circuits, or othernon-standard-sized breathing circuits without undue experimentation.

In one or more embodiments, the diffusing device 100 comprises anannular body 110 that may be a cylinder having a wall and a hollowinternal region. The body may be configured and dimensioned to connectto tubing in a ventilator breathing circuit (10, 15 and 22 mm), fit intoventilator tubing, or have ventilator tubing fitted into the body. Invarious embodiments, the inlet end of the device comprises a maleconnection configured and dimensioned to join to a ventilator tube, andthe outlet end comprises a female connection configured and dimensionedto join to a ventilator tube or humidifier chamber inlet. In anon-limiting example, the inlet end of the device comprises a 22 mm(O.D.) male connection, and the outlet end comprises a 22 mm (I.D.)female connection. In addition, the diffusing device 100 can be acomponent or part of an injector module which couples to a ventilatorbreathing circuit, as is known in the art.

In one or more embodiments, the annular body 110 may have an outsidediameter ‘A’ at an inlet end and/or an outlet end. The outside diameter‘A’ may be in the range of about 10 mm (0.394 in.) to about 25 mm (1.0in.), or about 22 mm (0.866 in.), where the ventilator tubing may befitted around the outside of the inlet end OD and inside the outlet endID. In various embodiments, a ventilator tube may be connected to aninlet end and/or outlet end of a diffusing device utilizing afriction-fit connection, as would be known in the art.

In one or more embodiments, the annular body may have an inside diameter‘B’ at an outlet end and/or an inlet end. The inside diameter ‘B’ may bein the range of about 10 mm (0.394 in.) to about 25 mm (1.0 in.), orabout 22 mm (0.866 in.), where the ventilator tubing may be fitted intothe inside of the inlet end ID. In various embodiments, a ventilatortube may be connected to an inlet end and/or outlet end of a diffusingdevice utilizing a friction-fit connection, as would be known in theart.

In one or more embodiments, gas(es) may enter the inlet end of thediffusing device 100 and exit the outlet end of the diffusing device,where the gas(es) may comprise a mixture of breathable gases. In variousembodiments, the breathable gases may comprise air, or air andadditional oxygen.

In various embodiments, the wall thickness ‘C’ of the diffusing device100 may be in the range of about 1 mm (0.040 in.) to about 3.175 mm(0.125 in.), or in the range of about 1 mm (0.040 in.) to about 2 mm(0.079 in.), or in the range of about 0.0625 to about 0.094.

In one or more embodiments, the diffusing device may have a length ‘D’in the range of about 6.35 mm (0.25 in.) to about 41.3 mm (1.625 in.),or in the range of about 22.225 mm (0.875 in.) to about 41.275 mm (1.625in.), or in the range of about 25.4 mm (1.00 in.) to about 38.1 mm (1.50in.).

In one or more embodiments, the device further comprises a taperedsection 150 comprising a wall, which may have a truncated cone, afunnel, or a bell shape, where the tapered section 150 narrows from aninside diameter ‘E’ at a first (inlet) end to an inside diameter ‘F’ ata second (outlet) end opposite the first end, wherein the opening at thefirst (inlet) end has a larger diameter than the opening at the second(outlet) end. In various embodiments, the first end having a largerdiameter is a mouth 152, and the second end having the smaller diameteris a throat 158.

In one or more embodiments, an accelerator may comprise a taperedsection or a bi-directional tapered section.

In various embodiments, the inside diameter ‘E’ at the mouth 152 may bein the range of about 14 mm (0.511 in.) to about 18 mm (0.709 in.), orabout 16.03 mm (0.631 in.).

In various embodiments, the inside diameter ‘F’ at the throat 158 may bein the range of about 3.17 mm (0.125 in.) to about 9.5 mm (0.375 in.),or about 6.35 mm (0.250 in.).

In one or more embodiments, the tapered section 150 may have a length‘I’ from the leading edge of the mouth 152 to the trailing edge of thethroat 158. In various embodiments, the length ‘I’ of the taperedsection 150 may be in the range of about 8 mm (0.315 in.) to about 13 mm(0.519 in.), or about 10.3 mm (0.405 in.).

In one or more embodiments, the inside surface of the tapered sectionforms a sharp corner at the leading edge of the mouth 150, so there areno flat surfaces perpendicular to the axis of the tapered section. Invarious embodiments, the wall of the tapered section may have athickness in the range of about 1 mm to about 2 mm or about 1.5 mm.

In one or more embodiments, the tapered section 150 may be locatedinside the body 110 of the diffusing device 100. In various embodiments,the tapered section may be suspended from a cylindrical wall 115 of theannular body 110 by a support 160, wherein the support 160 may extendfrom an inner surface of the cylindrical wall 115 into the open internalregion 118. In various embodiments, the annular body 110, taperedsection 150, and support joining the tapered section 150 to the annularbody may be one integral piece, where the annular body 110, taperedsection 150, and support 160 are molded as a single piece, so thecomponents comprise a single unitary construction. In variousembodiments, the tapered section 150 and the annular body 110 arecoaxial. In one or more embodiments, the projection 195 may form thesupport 160 by interconnecting the body 110 and the tapered section 150.

In one or more embodiments, there may be a gap 151 between the rim ofthe mouth 152 and the inside surface of the cylindrical wall 115, wherethe gap 151 has a size ‘G’ in the range of about 0.5 mm (0.02 in.) toabout 3 mm (0.118 in.), which provides an opening around the rim of themouth 152. In various embodiments, the opening allows at least a portionof the incoming gas(es) to by-pass the tapered section 150 by flowingalong the periphery of the internal region and around the taperedsection 150.

In one or more embodiments, the opening has a cross-sectional area inthe range of about 9.5% to about 19.0% of the cross-sectional area ofthe internal region

In one or more embodiments, the gap 151 has a cross-sectional area inthe range of about 15% to about 35% of the cross-sectional area of theinternal region where the internal region defined as B diameter is 20mm.

In one or more embodiments, the tapered section 150 may be a distance‘H’ from the leading edge of the annular body 110. In variousembodiments, the distance ‘H’ from the leading edge of the annular body110 may be in the range of 3.175 mm (0.125 in.) to about 12.7 mm (0.50in.). In various embodiments, dimension H may be reduced to therebyminimize the size and weight of the device.

In one or more embodiments, the tapered section 150 may be a distance‘J’ from the trailing edge of the annular body 110. In variousembodiments, the distance ‘J’ from the trailing edge of the annular body110 may be in the range of 3.175 mm (0.125 in.) to about 12.7 mm (0.50in.), In various embodiments, dimension J may be reduced to therebyminimize the size and weight of the device.

In one or more embodiments, a nipple 190 for attaching a delivery tubeto the diffusing device may protrude from the outer surface of thecylindrical wall 115. In various embodiments, the nipple may have adiameter ‘M’ of about 4.5 mm diameter (0.177 in.) and protrude from theouter surface of the cylindrical wall 115 a height ‘N’ of about 8.7 mm(0.34 in.).

In various embodiments, an injection channel 180 leading to an injectionport may be formed in the nipple, where the injection channel 180 has aninside diameter of ‘L’. In various embodiments, the inside diameter ‘L’may be in the range of about 0.8 mm (0.03125 in.) to about 2.4 mm (0.094in.), or about 1.6 mm (0.0625 in.).

In one or more embodiments, the opening forming the injection port 185at the internal end of the injection channel 180 may be located proximalto region where fresh gas velocity is maximized in diffuser device (e.g.a distance ‘K’ from the outlet end of the tapered section 150. Invarious embodiments, the distance ‘K’ may be in the range of about 2 mm(0.787 in.) to about 5 mm (0.197 in.), or about 3 mm (0.118 in.) fromthe outlet end of the tapered section 150).

In one or more embodiments, the NO injection port may terminate at thethroat wall, or an extension tube may project further into the throatfrom the internal surface of the tapered section. In variousembodiments, the extension tube may project into center of the throat.

In one or more embodiments, the injection port may be 6.81 mm from theleading edge of the tapered section.

In one or more embodiments, the tapered section may be suspended withina hollow cylindrical portion of a housing, wherein the housing isadapted to connect to ventilator tubing. In various embodiments, thehousing may have a shape other than cylindrical or annular while havingan inlet and outlet configured and dimension to connect to suitableventilator tubing. For example a rectangular housing of a diffusingdevice may have cylindrical inlet and outlet openings with an I.D. toconnect to tubing.

In one or more embodiments, a diffusing device may be utilized in aventilator circuit, with a nasal cannula, or with a face mask.

FIG. 9A illustrates an exemplary embodiment of a tapered section 300having a funnel shape.

In one or more embodiments, the funnel shaped tapered section 300 has aninternal surface that is convex, and directs gas(es) entering the mouth320 towards the throat 310. In various embodiments, the convex contourof the internal surface may have a constant curvature or a changingcurvature.

FIG. 9B illustrates an exemplary embodiment of a tapered section 340having a cone shape.

In one or more embodiments, the cone shaped tapered section 340 has aninternal surface that is straight from the mouth 320 of the taperedsection 340 to the throat 310, and directs gas(es) entering the mouth320 towards the throat 310.

FIG. 9C illustrates an exemplary embodiment of a tapered section 370having a bell shape, where the bell shape may have constant curvature ora changing curvature.

In various embodiments, a tapered section, as depicted in 300, 340, and370 may be adjoined throat-to-throat to provide a bi-directional taperedsection to allow for insertion and use in a ventilation circuit ineither orientation. FIG. 10 illustrates an exemplary embodiment of abi-directional tapered section. A bi-directional tapered section 700 maycomprise two tapered sections 150 coupled at their throats, where theinjection valve provides for injection of a gas at the narrowest portionof the bidirectional tapered section 700. In various embodiments, thetwo tapered sections may be coupled at a throat comprising a cylindricalsection 740. In various embodiments, the injection port would be locatedwhere the two tapered sections join, and the FGF velocity should be at amaximum at the lowest expected FGF rate. In some embodiments, a taperedsection is utilized in environments in which the FGF rate is expected tobe low, e.g. less than 2 SLPM.

In one or more embodiments, the bell shaped tapered section 370 has aninternal surface that is concave, and directs gas(es) entering the mouth320 towards the throat 310.

FIG. 11 illustrates an exemplary tapered section 400 depicting a contourof an inside surface of a tapered section wall 415.

Principles and embodiments of the present invention also relate todiffusing device comprising a tapered section 400 comprising adecreasing cross-sectional area that increases the velocity of the gasflow past the injection port and exiting the throat, so a highconcentration gas is quickly dispersed and diffused with the ventilatorgas.

In one or more embodiments, the tapered section 400 can be anaxially-symmetrical tube with a variable cross-sectional area, wherearea is decreasing from the mouth area to the throat area. In variousembodiments, the wall 415 may have a straight, parabolic, hyperbolic,catenoidal, or funnel contour.

In one or more embodiments, the tapered section 400 may comprise acylindrical section 440 with a constant diameter and cross-sectionalarea that extends a length ‘P’ from the point that the cross-sectionalarea is at a minimum, and/or the slope of the tapered section becomes 0(zero) (i.e., horizontal).

In various embodiments, the tapered section creates an increasingpressure gradient, so flow or boundary separation cannot occur becauseof the favorable pressure gradient. The avoidance of boundary separationalso avoids reverse-flow regions and vortices that may deplete theenergy of the gas flow and increase flow resistance. The pressure dropfor a volumetric flow rate of 60 SLPM may be approximately 0.65 cm H₂O,and at 30 SLPM may be approximately 0.16 cm H₂O.

In one or more embodiments, the contour of the tapered section wall 430has a constant curvature with a radius R₁, where R₁ may be in the rangeof 7.5 mm (0.296 in.) to about 8.3 mm (0.328 in.), or about 7.6 mm(0.299 in.).

An aspect of the present invention relates to a method of diffusing ahigh concentration gas into a transverse gas stream.

FIG. 12 illustrates an exemplary embodiment of a second gas passingthrough an injection channel 180 into a first gas passing through atapered section 150. (Gas flows are indicated by straight and curvedarrows.)

In one or more embodiments, at least a portion of a first gas enters adiffusing device 100 and passes through a tapered section 150 comprisinga wall 155 having a thickness, an outer surface and an inner surface, aninlet end having a first diameter, and an outlet end having a seconddiameter opposite the inlet end, wherein the second diameter is smallerthan the first diameter; and passing a second gas stream through aninjection channel 180 to an injection port 185 in the inner surface ofthe tapered section 150. In various embodiments, the second gas streamenters and at least partially diffuses with the first gas stream withinthe tapered section 150. In various embodiments, the injection of thesecond gas at an intended flow rate and velocity into the stream of thefirst gas creates sufficient diffusing at the point contact orconfluence of the two gas streams. In various embodiments, the intendedvolumetric flow rate of the second gas (NO at 1-80 ppm dose) may be inthe range of about 0.1 SMLPM to about 33.3 SMLPM for 4880 ppm NO, wherethe volumetric flow rate of the second gas (NO) is proportional to thevolumetric flow rate of the first gas (FGF) when the first gas flow rateis in the range of about 0.5 SLPM to about 2.0 SLPM.

In one or more embodiments, at least a portion of the first gas passesaround at least a portion of the outer surface of the tapered section,wherein the tapered section 150 is within an annular body 110 having anouter surface and an inner surface, and an inside diameter that islarger than the first diameter of the tapered section. In variousembodiments, at least a portion of the first gas passes through the gap151 between the rim 153 of the mouth 152 and the inside surface of thecylindrical wall 115.

In one or more embodiments, the first gas is a breathable gas comprisingmolecular N₂ and molecular O₂, and the second gas comprises molecular NOand molecular N₂.

In one or more embodiments, the first gas is provided by a ventilator ata flow rate in the range of about 0 liters per minute (SLPM) to about120 liters per minute (SLPM). In some instances, as described herein,during expiratory flow there may be flows in the range 0.5 SLPM to 2SLPM that may result in higher NO2 being generated. Accordingly, in atleast some instances, the disclosed techniques may be directed towardsthese lower flow rates.

In various embodiments, the concentration of NO in the second gas is inthe range of greater than 800 ppm to about 5000 ppm, or about 2000 ppmto about 4880 ppm, or about 4800 ppm.

In one or more embodiments, the flow rate of the second gas is linearlyproportional to the flow rate of the first gas.

In one or more embodiments, the second gas stream initially enters thefirst gas stream at an angle in the range of about 60° to about 120°, orat an angle in the range of about 75° to about 105°, or about 80° toabout 100°, or about 85° to about 95°, or at about 90° to the axis ofthe first gas stream. In various embodiments, the second gas may beinjected perpendicularly to the first gas stream, where the twoperpendicular gas streams act to impart turbulence at the point ofcontact, to reduce NO₂ levels to a value equal to or less than theamount generated by the current 800 ppm therapy.

Without being limited by theory, it is believed that sufficientdiffusion results when FGF is impinged by intersecting NO flow, wherethe NO and FGF have sufficient velocity at ventilator bias flows. Inaddition, a short annular outlet just after the point of NO injectionmay allow for a quick divergence of the once compressed FGF gas withinthe tapered section, now combined with NO, to exit abruptly and freelydiffuse with bypass flow around the tapered section.

In one or more embodiments, the second gas exits the injection port 185at a flow rate in the range of about 0.1 milliliters per minute (SMLPM)to about 6.3 SLPM, or about 0.05 milliliters per minute (SMLPM) to about2 SLPM, or about 1.0 milliliters per minute (SMLPM) to about 1 SLPM. Agas flow rate of 2 SLPM has a velocity of approximately 0.42 meters/sec.through an injection channel and injection port with a 0.16 cm I.D. Agas with this velocity would not experience noticeable compression atthis velocity when passing through the diffusing device, which is lessthan 0.2×the speed of sound (i.e., Mach Number <0.2). A gas flow rate of0.5 SLPM has a velocity of approximately 0.10 meters/sec. through aninjection channel and injection port with a 0.16 cm I.D. It can behelpful to manage NO₂ conversion during periods of very low ventilatorflow rates (e.g., bias flow during exhalation ≤2 SLPM), increased oxygenconcentrations (FiO₂≥60%), and higher NO set dosage (≥20 ppm).

In one or more embodiments, the velocity of the first gas is greater atthe second diameter of the tapered section 150 than the velocity of thefirst gas at the first diameter of the tapered section 150.

In one or more embodiments, the velocity of the first gas is greater atthe second diameter of the tapered section than the velocity of thefirst gas at the first diameter of the tapered section, wherein thesecond gas enters the first gas at a point of greater velocity. Invarious embodiments, the tapered section generates an increase gasvelocity and pressure gradient towards the middle of the annular body,such that the highest gas velocity is along the axis of the taperedsection 150. For example, a reduction of the tapered section 150 I.D.from 1.6 cm at the mouth to 0.635 cm at the throat would result in anincrease in the first gas velocity. In some instances, the ratio ofinlet to outlet gas velocities is proportional to the ratio of inlet tooutlet areas.

As can be seen in FIG. 12, the second gas enters the first gas at theinjection port 185, which is closer to the throat of the tapered section150, and where the velocity of the first gas flow has increased comparedto the first gas velocity at the mouth of the tapered section.

FIG. 13 illustrates an exemplary embodiment of a diffusing device 100inserted into a ventilator circuit 600. In various embodiments, theventilator system may provide elevated (>21%) fractional inspired oxygen(FiO₂) concentrations along with NO doses to mechanically ventilatedpatients. Oxygen concentration in patient ventilator circuits may rangefrom medical air (21% O₂) to medical oxygen (100% O₂), but are generallyelevated to 60% for patients receiving INO therapy. The NO in a highconcentration NO gas source 610 may be diluted with nitrogen N₂.

In one or more embodiments, a diffusing device 100 (e.g., as a componentin an injector module 605, downstream of a flow sensor 615 capable ofmeasuring fresh gas flow in the breathing circuit, etc.) may beconnected to and in fluid communication with ventilator tubing comingfrom a ventilator 630. The ventilator may be connected to and in fluidcommunication with a fresh gas source 620. The diffusing module 100 mayalso be connected to and in fluid communication with a control module640 that controls the dosage of NO fed into the diffusing module 100.The control module 640 may be connected to and in fluid communicationwith a NO gas source 610. In various embodiments, the fresh gas source620 and NO gas source 610 may have regulators to control the pressurefrom the cylinders. In various embodiments, the diffusing device may beconnected to and in fluid communication with a humidifier 650 that addswater vapor content to the inspiratory gas flow to the patient. Invarious embodiments, the distance from the diffusing device 100 to thepatient may be approximately 1 meter. In various embodiments, thehumidifier may have a compressible volume of about 280 ml. In variousembodiments, the diffusing device 100 and the flow sensor 615 areintegral to the injector module 605.

In one or more embodiments, the diffusing device diffuses the incomingfresh gas flow from the ventilator 630 and fresh gas source 620 with theincoming NO-containing gas from the NO gas source 610 flowing throughthe control module 640. The gas flow being delivered to the patient maybe sampled at a sampling tee 660 inserted down stream from thehumidifier 650 and/or diffusing device 100. In various embodiments, NO,NO₂, and/or O₂ concentrations may be monitored before reaching thepatient. The sampling tee 600 can be placed at various positions in thebreathing circuit, depending on how quickly the NO-containing gas andFGF combine to provide a homogenous gas stream at the set dose.Furthermore, a plurality of sampling points may be used, such assampling points located at various distances from the NO injectionpoint. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 or more samplingpoints may be used. The distance between sampling points can be 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or 30 cm. The plurality of samplingpoints can be used to separately analyze the combined gas stream as afunction of length down the breathing circuit, or two or more samplingcan be combined to provide an average for the composition of the gas.

As explained in the Examples below, an increase in temperature hassurprisingly been found to decrease the amount of NO₂ that is generatedunder otherwise similar conditions. Accordingly, embodiments of thepresent invention also relate to minimizing NO₂ generation by heatingone or more portions of the NO delivery system and/or ventilatorcircuit. While not wishing to be bound by any particular theory, it isbelieved that an increase in gas temperature can increase the availablekinetic energy with the gas molecules, which can promote initial mixingresulting in further NO₂ reduction.

For example, a heating element may be added to the NO delivery system,the tubing from the NO delivery system to the injector module, theinjector module and/or the tubing of the inspiratory limb of theventilator circuit, and/or may be placed at any other location upstream,downstream or at the point of injection. The heating element may be aheated humidifier or may be a dedicated heating component. Exemplaryheating elements include, but are not limited to, a thermoelectriccooling device or a resistive heating element. A heating element in theNO delivery system can help minimize NO₂ generated internally within theNO delivery system. Likewise, heating elements placed in, and/or inthermal communication with, the tubing that deliver the NO to theinjector module and from the injector module to the patient can helpminimize NO₂ generation at those points.

In various embodiments, the heating element can heat the NO source gasand/or the combined NO and FGF to a desired temperature. Exemplarytemperatures include, but are not limited to, about 25° C., about 26°C., about 27° C., about 28° C., about 29° C., about 30° C., about 31°C., about 32° C., about 33° C., about 34° C., about 35° C., about 36°C., about 37° C., about 38° C., about 39° C., about 40° C., about 45° C.or about 50° C.

EXAMPLES

The present invention is further described by means of the examples,presented below. The use of such examples is illustrative only and in noway limits the scope and meaning of the invention or of any exemplifiedterm. Likewise, the invention is not limited to any particular preferredembodiments described herein. Indeed, many modifications and variationsof the invention will be apparent to those skilled in the art uponreading this specification. The invention is therefore to be limitedonly by the terms of the appended claims along with the full scope ofequivalents to which the claims are entitled.

Example 1—NO₂ Generation System Comparison

A NO delivery system utilizing a high NO source concentration (e.g. 4880ppm) and an injector module with an exemplary diffuser as describedherein (e.g. a diffuser as shown in FIGS. 8A-B) was compared to aconventional NO delivery system utilizing a low NO source concentration(e.g. 800 ppm) and a conventional injector module. The FGF was providedby a neonatal ventilator with exemplary ventilation parameters (e.g.respiratory rate of 40, tidal volume of 30 ml, FiO₂ of 60%, 0.5 SLPMbias flow, etc.). As can be seen from FIG. 14, the high NO sourceconcentration system utilizing a diffuser (System 2) produced acomparable amount of NO₂ as the conventional NO delivery system at alower NO source concentration (System 1), despite a significantly higherNO source concentration.

System 1 and System 2 were also compared to a NO delivery systemutilizing a high NO source concentration (e.g. 4880 ppm) and an injectormodule with an exemplary accelerator as described herein (e.g. anaccelerator as shown in FIGS. 8C-D), which is designated System 3. FIGS.15A-F show the NO₂ produced for each system at various NO set doses andFGF flow rates. As can be seen from FIGS. 15A-F, both Systems 2 and 3 atthe high NO source concentration produced a comparable or lower amountof NO₂ at a set dose of 40 ppm as the conventional NO delivery system ata lower NO source concentration. While not wishing to be bound by anyparticular theory, it is believed that the relatively low NO₂ values forSystems 2 and 3 at 40 ppm is a result of the FGF and NO-containing gaseshaving similar velocities. As can be seen from Table 3 below, thevelocity of the NO-containing gas was most similar to the FGF velocityat 40 ppm for the particular configurations tested as Systems 2 and 3.

TABLE 3 Velocity of NO-Containing Gas for Systems 2 and 3 NO Velocity(cm/sec) NO Dose 5 10 20 40 80 FGF 3.67 0.4 0.9 1.8 3.6 7.3 Velocity14.7 1.8 3.6 7.2 14.5 29.2 (cm/sec) 58.79 7.2 14.4 28.9 58 117 110.2313.5 27 54.1 108.7 219.3 220.46 27 54 108.3 217.5 438.6 440.92 54 108.1216.6 435 877.2

Example 2—NO₂ Generation with Heated System

The NO delivery system used in System 2 of Example 1 was then used witha heated ventilator breathing circuit (e.g. about 38° C.). As can beseen from FIG. 16, heating the ventilator breathing circuit reduced theNO₂ levels under all conditions tested.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It will be apparent to those skilled in the art thatvarious modifications and variations can be made to the devices,systems, and methods of the present invention without departing from thespirit and scope of the invention. Thus, it is intended that the presentinvention include modifications and variations that are within the scopeof the appended claims and their equivalents.

Example 3—NO₂ Minimization Using Gas Velocity Ratio

The NO delivery system used in System 2 of Example 1 was modified tohave various NO source concentrations and to provide various ratios ofthe FGF velocity to the NO-containing gas velocity. A plurality of gassampling points was used for NO and NO₂ concentration measurements,which was averaged to account for any inhomogeneous distribution of thegases within the cross-section of the tube. The NO₂ concentration wasmeasured at three different points downstream from the NO injectionpoint T0:T1 (203 mm downstream from NO injection point), T2 (673 mmdownstream from NO injection point) and T3 (2268 mm downstream from NOinjection point). For the experiments described below, the region fromT0 to T1 was considered to have a non-homogenous gas distribution andthe region from T2 to T3 was considered to have a homogenous gasdistribution. The NO₂ conversion rate was determined by subtracting theNO₂ contribution from the NO source cylinder from the measured NO₂concentration, and dividing the net gain in NO₂ concentration by theresidence time between sample points (volumetric flow rate divided bythe volume of the segment).

FIG. 17 shows the NO₂ generated in the initial T0-T1 region with variousNO source cylinder concentrations ranging from 800 ppm to 9760 ppm witha gas velocity ratio (FGF:NO) of approximately 1:1. As can be seen fromFIG. 17, by having a gas velocity ratio of approximately 1:1, the NO₂generation rate is comparable between various cylinder concentrations atthe same set dose (20 ppm) and the same FGF flow rate (0.5 or 2 SLPM).

FIGS. 18A-D show the NO₂ generated in the initial T0-T1 region withvarious NO source cylinder concentrations ranging from 800 ppm to 9760ppm with a varying gas velocity ratio (FGF:NO) and a set dose of 10 ppmNO. As can be seen from each of FIGS. 18A-D, gas velocity ratios below2:1 provide a lower NO₂ generation rate than gas velocity ratios above2:1, even when the NO source concentration, FGF flow rate and the NO setdose are the same.

FIG. 19 shows the NO₂ generated in the initial T0-T1 region with a 4880ppm NO source cylinder concentration and a set dose of 40 ppm, with avarying gas velocity ratio (FGF:NO). As can be seen by comparing FIG. 19and FIG. 18C, the relationship between NO₂ generation rate and gasvelocity ratio is also seen at other set dose concentrations.

FIGS. 20A-B show the NO₂ generated in the initial T0-T1 region withvarious NO source cylinder concentrations ranging from 800 ppm to 9760ppm with a varying gas velocity ratio (FGF:NO) and a set dose of 10 ppmNO. As can be seen from FIGS. 20A-B, gas velocity ratios below 2:1provide a lower NO₂ generation rate than gas velocity ratios above 2:1,even when the NO source concentration, FGF flow rate and the NO set doseare the same. As FIGS. 20A-B are plotted on a logarithmic base 10 scalefor both the x and y axes, this demonstrates that the instantaneous NO₂generation is non-linear.

FIG. 21 shows the NO₂ generated in the initial T0-T1 region with a 4880ppm NO source cylinder concentration and a set dose of 40 ppm, with avarying gas velocity ratio (FGF:NO). FIG. 21 also shows the average NO₂generation rate from T2 to T3. As can be seen from FIG. 21, the NO₂generation rate from T0-T1 is significantly higher than the NO₂generation rate from T2 to T3. Also, the NO₂ generation rate from T2 toT3 (shown in triangles) does not vary with the gas velocity ratio,showing that a constant rate of NO₂ generation rate is achieved afterthe combined gas stream reaches a homogenous phase at T2. FIG. 21further provides the size of the inner diameter of the FGF pipe for eachconfiguration: 0.942 in, 0.669 in or 0.335 in. As can be seen,decreasing the FGF pipe diameter did not reduce NO₂ generation, butinstead resulted in higher NO₂ generation rates. This is consistent withthe observed phenomenon of NO₂ generation being minimized with lowerFGF:NO velocity ratios, particularly those below 2:1.

Example 4—NO₂ Generation During Cycling Flow

The NO delivery system of Example 3 was modified to simulate aventilator with varying flow rates. A square wave flow with a minimumflow of 0.5 SLPM and a maximum flow of 5 SLPM was used, with a varyinginspiratory to expiratory ratio (high to low flow ratio) ranging from2:2 to 1:3. FIGS. 22A-B show the NO2 generated in ppm and as apercentage of the set dose of NO. As can be seen from FIGS. 22A-B, themost NO₂ was generated with a higher expiratory (low flow) ratio. As canbe seen from FIG. 22B, a high percentage of the NO was converted to NO₂at the low set doses, with almost 25% of the NO being converted to NO₂when the inspiratory:expiratory ratio was 1:3 and the NO set dose was 1ppm.

Example 5: NO₂ Generation System Comparison

The NO₂ generation rate of a NO delivery system utilizing a suspendedfunnel (System 3 of Example 1) and the NO delivery system of Example 3was compared from T0 to T1 at a set dose of 10 ppm NO and a cylinderconcentration of 4880 ppm NO. The results of this comparison are shownin Table 4 below.

TABLE 4 NO₂ Generation for Systems 3 of Example 1 and Systems of Example3 NO₂ Generation Rate (ppb/s) Diffuser with Diffuser with Diffuser withGas Velocity Gas Velocity Gas Velocity Ratio Ratio Ratio Suspended(FGF:NO) (FGF:NO) (FGF:NO) Funnel 2:1 1:1 0.5:1 FGF Flow 0.5 32 32 24 13Rate 2 73 79 58 33 (SLPM)

As can be seen from Table 4, the suspended funnel design performedcomparably to a diffuser with a gas velocity ratio of about 2:1.However, diffusers with velocity ratios below 2:1 (1:1 or 0.5:1)provided lower NO₂ generation rates than the suspended funnel design.

Reference throughout this specification to “one embodiment,” “certainembodiments,” “one or more embodiments” or “an embodiment” means that aparticular feature, structure, material, or characteristic described inconnection with the embodiment is included in at least one embodiment ofthe invention. Thus, the appearances of the phrases such as “in one ormore embodiments,” “in certain embodiments,” “in one embodiment” or “inan embodiment” in various places throughout this specification are notnecessarily referring to the same embodiment of the invention.Furthermore, the particular features, structures, materials, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

What is claimed is:
 1. A method of delivery nitric oxide (NO) to apatient, the method comprising: combining a first gas stream comprisingmolecular oxygen (O₂) and a second gas stream comprising NO to provide acombined gas stream; and delivering the combined gas stream to thepatient, wherein the diffusing of NO and O₂ in the combined gas streamoccurs sufficiently rapidly that less than 1 ppm of NO₂ is delivered tothe patient.
 2. The method of claim 1, wherein the second gas stream isprovided by an NO source having an NO concentration of greater than 800ppm to about 10,000 ppm.
 3. The method of claim 1, wherein the combinedgas stream has an NO concentration of about 1 ppm to about 80 ppm. 4.The method of claim 1, wherein the first gas is a breathable gascomprising molecular N₂ and molecular O₂, and the second gas comprisesmolecular NO and molecular N₂.
 5. The method of claim 1, wherein thesecond gas stream initially enters the first gas stream at an angle inthe range of about 60° to about 120°.
 6. The method of claim 1, whereinthe volumetric flow rate of the second gas is linearly proportional tothe volumetric flow rate of the first gas.
 7. The method of claim 1,wherein the first gas stream has a first velocity and the second gasstream has a second velocity, and the ratio of the first velocity to thesecond velocity is less than 2:1.
 8. The method of claim 7, wherein theratio of the first velocity to the second velocity is less than or equalto about 1:1.
 9. The method of claim 8, wherein the ratio of less thanor equal to about 1:1 is provided when the first gas stream has avolumetric flow rate of less than 2 SLPM.
 10. The method of claim 1,wherein the second gas stream enters the first gas stream at or near thecentral midpoint of the highest velocity of the first gas stream. 11.The method of claim 1, wherein the second gas stream is injected intothe first gas stream as a plurality of pulses.
 12. The method of claim1, wherein the device comprises: a body comprising a wall having athickness, an outer surface, and an inner surface surrounding a hollowinternal region; a projection extending from the inner surface of thebody and into the hollow internal region; and an injection channelpassing through the wall and projection to an injection port such thatthe injection port injects the high concentration gas into thetransverse gas stream at a distance from the inner surface of the body.13. The method of claim 12, wherein the hollow internal region has adiameter, and a length of the projection from the inner surface to theinjection port outlet is in the range of about 30% to about 45% of thediameter of the hollow internal region.
 14. The method of claim 12,wherein the device comprises a plurality of injection ports.
 15. Themethod of claim 1, wherein the device is integral to an injector modulecomprising a flow sensor.
 16. A method of delivery nitric oxide (NO) toa patient, the method comprising: receiving a dose of NO from a user;combining a first gas stream comprising molecular oxygen (O₂) and asecond gas stream comprising NO to provide a combined gas stream; anddelivering the combined gas stream to the patient, wherein the diffusingof NO and O₂ in the combined gas stream occurs sufficiently rapidly thatless than 1 ppm of NO₂ is delivered to the patient.
 17. The method ofclaim 16, the combined gas stream provides the dose of NO at aconcentration of about 1 ppm to about 80 ppm.
 18. The method of claim16, wherein the volumetric flow rate of the second gas is linearlyproportional to the volumetric flow rate of the first gas.
 19. Themethod of claim 16, wherein the first gas stream has a first velocityand the second gas stream has a second velocity, and the ratio of thefirst velocity to the second velocity is less than 2:1.
 20. The methodof claim 1, wherein the second gas stream enters the first gas stream ator near the central midpoint of the highest velocity of the first gasstream.